本文關(guān)鍵詞：多聚谷氨酰胺疾病DRPLA小鼠模型的建立、機(jī)理研究和藥物治療　出處：《復(fù)旦大學(xué)》2005年博士論文　論文類(lèi)型：學(xué)位論文

  更多相關(guān)文章： 多聚 谷氨 酰胺 疾病 DRPLA 小鼠 模型 建立 機(jī)理 研究 藥物 治療

【摘要】：齒狀核紅核蒼白球丘腦底核萎縮(dentatorubral-pallidoluysian atrophy，DRPLA)是一種常染色體顯性遺傳的神經(jīng)退行性疾病，臨床表現(xiàn)有共濟(jì)失調(diào)、震顫、肌肉痙攣、舞蹈癥、癡呆等。DRPLA是由atrophin-1基因中編碼谷氨酰胺的CAG重復(fù)序列的擴(kuò)增所造成，包含多聚谷氨酰胺擴(kuò)增的Atrophin-1突變蛋白導(dǎo)致齒狀核、紅核、蒼白球以及丘腦底核等腦區(qū)的神經(jīng)元損傷。 為了研究DRPLA的發(fā)病機(jī)理和治療方法，我們建立了神經(jīng)元特異性表達(dá)人類(lèi)突變型Atrophin-1蛋白的轉(zhuǎn)基因小鼠——Atro-118Q。行為學(xué)和病理學(xué)分析顯示，Atro-118Q小鼠基本模擬了DRPLA患者的神經(jīng)退行性病征，包括：共濟(jì)失調(diào)、震顫等運(yùn)動(dòng)缺陷，神經(jīng)元的核內(nèi)包涵體以及神經(jīng)元的胞體萎縮，，說(shuō)明Atro-118Q小鼠是一種較好的DRPLA小鼠模型。野生型Atrophin-1蛋白的高表達(dá)不能減弱Atro-118Q小鼠的神經(jīng)退行性表型，說(shuō)明多聚谷氨酰胺擴(kuò)增的Atrophin-1蛋白所造成的表型可能并不是簡(jiǎn)單地由突變蛋白的顯性負(fù)效應(yīng)(dominant negative effect)所引起的。生化分析顯示，在Atro-118Q小鼠的腦組織中，組蛋白乙酰化水平明顯降低，提示基因轉(zhuǎn)錄的抑制可能與Atro-118Q小鼠的神經(jīng)退行性表型有關(guān)。腹腔注射組蛋白脫乙�；傅囊种苿∷徕c，能夠提高Atro-118Q小鼠腦組織中組蛋白的乙�；�，同時(shí)緩解了Atro-118Q小鼠的運(yùn)動(dòng)缺陷，延長(zhǎng)了小鼠的壽命。這一結(jié)果為開(kāi)展DRPLA的藥物治療提供了十分有意義的線索，同時(shí)也表明基因轉(zhuǎn)錄失調(diào)很可能是包括DRPLA在內(nèi)的多種多聚谷氨酰胺疾病的重要病因之一。 DRPLA的致病基因atrophin-1在進(jìn)化上具有較高的保守性，編碼的蛋白質(zhì)參與基因轉(zhuǎn)錄的調(diào)控。為了深入研究atrophin-1基因的功能，我們建立了atrophin-1基因剔除小鼠。atrophin-1~(-／-)小鼠出現(xiàn)腦組織、眼睛等方面的異常表型，對(duì)該小鼠的研究將有助于揭示轉(zhuǎn)錄調(diào)節(jié)基因atrophin-1與器官發(fā)育以及DRPLA等多聚谷氨酰胺疾病的關(guān)系。
[Abstract]:Dentatorubral-pallidoluysian atrophy of the hypothalamic nucleus pallidoluysian of the dentate nucleus red nucleus pallidoluysian. DRPLA is an autosomal dominant neurodegenerative disease characterized by ataxia tremor muscle spasm and chorea. DRPLA is caused by the amplification of CAG repeats encoding glutamine in the atrophin-1 gene. The polyglutamine amplified Atrophin-1 mutant protein causes neuronal damage in the dentate nucleus, red nucleus, globus pallidus and subthalamic nucleus. In order to study the pathogenesis and treatment of DRPLA. We established a neuron-specific transgenic mouse expressing human mutant Atrophin-1 protein Atro-118Q.Behavioral and pathological analysis showed. Atro-118Q mice basically simulated the neurodegenerative symptoms of DRPLA patients, including ataxia, tremor and other motor defects, neuronal inclusion bodies and neuronal cell body atrophy. The high expression of wild-type Atrophin-1 protein can not attenuate the neurodegenerative surface of Atro-118Q mice. Type. These results suggest that the phenotypes of polyglutamine amplified Atrophin-1 proteins may not be simply due to the dominant negative effects of mutant proteins (. Dominant negative effect. biochemical analysis shows. The level of histone acetylation was significantly decreased in Atro-118Q mice. It was suggested that the inhibition of gene transcription might be related to the neurodegenerative phenotype of Atro-118Q mice. Sodium butyrate, an inhibitor of histone deacetylase, was injected intraperitoneally. It can improve the level of acetylation of histone in brain tissue of Atro-118Q mice and alleviate the motor defect of Atro-118Q mice at the same time. The results provide a useful clue to the development of drug therapy for DRPLA. It also suggests that gene transcriptional disorders may be one of the major causes of polyglutamine disease including DRPLA. The pathogenicity gene atrophin-1 of DRPLA is highly conserved in evolution. The encoded protein is involved in the regulation of gene transcription. In order to further study the function of atrophin-1 gene. We established abnormal phenotypes of brain tissue and eyes in atrophin-1 gene knockout mice. The study of this mouse will be helpful to reveal the relationship between transcription regulating gene atrophin-1 and organ development and polyglutamine disease such as DRPLA.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2005
【分類(lèi)號(hào)】：R-332

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